Not a test

Antibiotics developers shouldn’t read too much into FDA’s rejection of the first drug to be reviewed under a new limited-use pathway that is supposed to make it easier to develop treatments for rare and resistant infections.

That’s because Achaogen Inc.’s Zemdri plazomicin doesn’t make a good test case for whether the limited population pathway for antibacterial and antifungal drugs (LPAD) pathway will be able to accomplish its goals.

On June 25, FDA granted full approval for Zemdri in complicated urinary tract infections (cUTIs) proven or strongly suspected to be caused by susceptible microorganisms. But it issued a complete response letter for use of the drug in bloodstream infections caused by susceptible microorganisms, an indication the company had sought under the LPAD pathway.

At least three factors suggest Zemdri is not the prototype for the pathway. First, the program wasn’t prospectively designed to take advantage of LPAD. Then, problems with enrollment rendered the company unable to execute on its original trial design and forced it to make several modifications. The resulting data were ambiguous, which made it impossible to tell if the apparent mortality benefit was real.

Achaogen plans to discuss with FDA potential next steps for a bloodstream indication. In the meantime, it is likely Zemdri will see off-label use for the indication (see Sidebar: “Accessing Alternatives”).

Approval for complicated urinary tract infections (cUTIs) means Zemdri could be used off-label to treat infections at other sites.

Zemdri’s label includes data from cUTI patients with concomitant bacteremia or with Enterobacteriaceae isolates detected. At the test of cure visit in patients with cUTI and bacteremia, 18 (72%) patients receiving Zemdri and 13 (56.3%) patients receiving meropenem had both microbiological eradication and clinical cure.

The label also lists pathogens Zemdri has shown activity against in vitro and in clinical testing, which includes Enterobacter cloacae and Enterobacter aerogenes.

Three infectious disease doctors told BioCentury they would consider using the drug off label for CRE patients, if they had no good alternatives.

James McKinnell, an assistant professor of medicine at the University of California Los Angeles David Geffen School of Medicine, thought Zemdri’s numerical advantage over colistin was substantial enough that FDA should have approved it under LPAD.

“There’s limitations of these trials that have to be understood, but clinicians understand that. We know that patients with these severe CRE infections die, and now we have a lifesaving drug,” he said.

University of California San Francisco Professor and Chief of the Division of Infectious Diseases Henry Chambers echoed the need to stock the arsenal.

“If I was out of options or didn’t have good ones, I would certainly consider it if I had access to that drug,” he added.

And Helen Boucher, a Tufts Medical Center professor of medicine and treasurer of the Infectious Diseases Society of America (IDSA), said regardless of whether the bloodstream infection data meet approval standards, doctors want to see it on the label for when they run out of approved options.

“Any data is useful to us in the trenches. The fact they were able to treat a number of patients with this drug, and have high quality data about those patients, that’s meaningful to me,” she said.

IDSA developed the original proposal for the LPAD pathway.

-- Emily Cukier

Achaogen’s registrational trial testing the next-generation aminoglycoside antibiotic in bloodstream infections caused by carbapenem-resistant Enterobacteriaceae (CRE) concluded before LPAD was legally enacted, thus it was not designed with it in mind. In addition, unforeseeable difficulties with enrollment caused the company to make multiple midstream changes to its protocol and analysis plan.

Achaogen changed endpoints and added a non-randomized cohort. It still ended up stopping the trial early due to poor accrual, eliminating the ability to conduct the planned superiority analysis.

In briefing documents released ahead of a May 2 advisory committee meeting, FDA reviewers said it could be appropriate to instead look at the results as evidence for non-inferiority. But the non-inferiority analysis was compromised by aspects of the protocol from the original superiority design, including the extent to which patients could receive prior antibiotic therapy.